With two leading biotech entrepreneurs and scientists at the helm, closely held Xcovery Holdings has a leg up as it continues development of next generation kinase inhibitors as treatments for cancer and, most recently, ophthalmology.
“Our CEO, Sheridan Snyder, met Dr. Chris Liang at a conference [in the mid-2000s] and discussed financing for a next-generation kinase inhibitor based on SUGEN’s kidney cancer drug, Sutent,” VP of business development Cheryl Calhoun says in an interview with BioTuesdays.com, referring to a meeting that led to the founding of Xcovery in 2006 by the two men.
Mr. Snyder founded Genzyme in 1981, followed by four additional biotech companies, including Biotage, Upstate, MolecularMD and Xcovery/Tyrogenex. Dr. Liang was a co-inventor of Sutent while he was director of medicinal chemistry at SUGEN.
Xcovery’s lead molecule, X-82, was developed by Tyrogenex, an Xcovery-affiliated company funded by Biocatalyst International, a closely held early-stage venture fund run by Mr. Snyder.
X-82 is a tyrosine kinase inhibitor of signaling through the receptors for vascular endothelial growth factor (VEGFR) and platelet-derived growth factor (PDGFR). VEGFR is an important angiogenesis protein for the production of new blood vessels that promote growth of most solid tumors, while PDGFR destabilizes newly formed blood vessels. The dual activity of X-82 on VEGFR/PDGFR inhibition could be more effective in prolonging overall response.
X-82 is completing the dose escalation portion of a Phase 1 study in patients with advanced solid tumors.
At the American Society of Clinical Oncology (ASCO) meeting in June, Xcovery presented preliminary data that showed X-82 was well tolerated, did not exhibit any dose-limiting toxicity and demonstrated preliminary signs of anti-tumor activity, including a complete response in a patient with pancreatic cancer and stable disease in five other cancer patients.
“The data support our hypothesis that our dual VEGFR/PDGFR inhibitor X-82 has a low toxicity profile and will be a differentiated and ideal product candidate for combination therapy,” Dr. Liang said in June.
Ms. Calhoun says the company is moving towards an expanded cohort that will include patients with ovarian and pancreatic cancers in a Phase 1b/2a clinical trial to start early in 2013. The company is also exploring studies, combining its drug and chemotherapy, at several academic centers in the U.S. It also plans to present additional clinical data at ASCO next year, she adds.
As a next-generation version of Sutent, Ms. Calhoun says X-82 has design improvements that address the toxicity of Sutent, which causes patients to undergo dosing holidays during their treatment. Patients take Sutent for four weeks and then have to stop for up to two weeks. “That’s not an ideal thing in cancer [treatment].”
She explains that Sutent has a half-life of 40 hours, and it tends to accumulate in tissue. X-82 has a half-life of about eight hours, so the body regularly clears X-82, enabling continuous treatment without toxicity.
Dr. Liang and his team have developed a portfolio of six low toxicity kinase inhibitors for multiple disease indications, and Xcovery plans to develop additional cancer targeted drugs. One of those drugs is targeting the anaplastic lymphoma kinase (ALK) gene in patients with lung cancer in a Phase 1 study, which began in June.
Pfizer’s crizotinib, which is sold as Xalkori, was approved in the U.S. and some other countries in 2011 to treat 5% to 7% of non-small cell lung cancer patients that have a mutation of the ALK gene. However, patients often develop resistance to the drug in about nine months. Xalkori sales are forecast to reach $540-million by 2015.
“We have a next-generation drug that’s ten times more potent than crizotinib, based on preclinical studies, and has the potential to address crizotinib resistant mutations,” Ms. Calhoun says.
Last month, Xcovery raised $6-million in series B financing, with a portion of the proceeds earmarked for a Phase 1/2 clinical trial using X-82 for the treatment of wet age-related macular degeneration (AMD), the leading cause of blindness in seniors.
Ms. Calhoun explains that the goal of the study is to assess the preliminary safety of X-82 as an oral formulation over a range of doses and evidence of biologic activity as measured by improvement in vision and reduction of sub-retinal fluid.
The trial, which will begin later this month and is expected to last about 12 months, will enroll a maximum of 20 patients at three ophthalmology centers in the U.S. “We will expand the number of patients with signals of efficacy,” Ms. Calhoun says.
As in its oncology program, X-82 acts to inhibit both VEGFR and PDGFR, two important targets implicated in wet AMD. Ms. Calhoun says the compound has been designed to have a favorable mode of administration as an oral medication than existing injectable drugs for AMD such as Lucentis.
In a statement last month, Mr. Snyder said the company is committed to providing better therapies to patients with advanced eye disease and the trial represents an important advancement in Xcovery Vision’s clinical development program. “The potential for an oral treatment for wet AMD is considered the ultimate therapeutic option for these patients,” he added.
Dr. Ken Mandell, president and COO of Xcovery Vision, said that “unlike current anti-VEGF injections that only treat the affected eye, our oral pill has the potential to prevent development of wet AMD in the opposite eye before disease progression.”
Ms. Calhoun adds that Xcovery Vision is also working with a U.S. government institution to study X-82 as a treatment for a rare eye tumor known as Von-Hippel Lindau (VHL), an inherited condition characterized by vascular tumors in the retina. VHL can cause blindness, and there is no medical therapy available.
“The use of an anti-VEGF/PDGF therapy is promising,” she says, adding that X-82 could be “ideal for this condition.”
Xcovery Pipeline
